Post on 26-Aug-2016
ORIGINAL ARTICLE
A phase II trial of erlotinib in patients with EGFR wild-typeadvanced non-small-cell lung cancer
Takashi Kobayashi • Tomonobu Koizumi • Toshihide Agatsuma •
Masanori Yasuo • Kenji Tsushima • Keishi Kubo • Seiichiro Eda •
Hiroshi Kuraishi • Shigeru Koyama • Tsutomu Hachiya • Nariaki Ohura
Received: 13 December 2011 / Accepted: 16 January 2012 / Published online: 26 January 2012
� Springer-Verlag 2012
Abstract
Purpose There is as yet no optimal treatment regimen for
patients with epidermal growth factor receptor (EGFR)
gene wild-type non-small-cell lung cancer (NSCLC) that
has progressed despite cytotoxic chemotherapy. This trial
was performed to evaluate the efficacy and toxicity of
erlotinib, a tyrosine kinase inhibitor of EGFR, in Japanese
patients with EGFR wild-type tumors.
Methods Patients with stage III/IV or postoperative
recurrence of NSCLC whose tumors have wild-type EGFR
were eligible. Erlotinib (150 mg/day) was administered
until disease progression or unacceptable toxicity occurred.
The primary end point was disease control rate (DCR).
Results Thirty-one patients (23 men and 8 women; med-
ian age, 71 years; range, 31–89) were enrolled between
January 2008 and June 2011. Twenty-one had adenocarci-
noma, nine had squamous cell carcinoma, and one had large
cell carcinoma. Ten, nine, eight, and four patients showed
performance status 0, 1, 2, and 3, respectively. Erlotinib was
administered following the median 3.1 regimens of cyto-
toxic chemotherapies. One patient achieved complete
response, four showed partial response, and eight had stable
disease. Thus, response rate was 17.2%, and DCR was
44.8%. Skin rash was the most common side effect (80.6%).
Two patients developed interstitial lung disease. Never-
theless, all of these events were reversible, and there were
no treatment-related deaths. The median progression-free
survival and survival times were 2.1 and 7.7 months,
respectively.
Conclusion Erlotinib might be an alternative option for
patients resistant to cytotoxic chemotherapy even in those
with EGFR wild-type NSCLC.
Keywords Chemo-refractory � Salvage therapy �EGFR-sensitive mutation � Chemotherapy � NSCLC
Introduction
Lung cancer is the leading cause of cancer-related death in
Japan and throughout the Western world [1, 2]. Platinum-
based doublet combinations are standard regimens for first-
line treatment in advanced-staged non-small-cell lung
cancer (NSCLC) and have provided only modest survival
advantages [3, 4]. Tyrosine kinase inhibitors of the epi-
dermal growth factor receptor (EGFR-TKIs) are promising
therapeutic options for patients with NSCLC [5, 6], espe-
cially in Asia [7–12]. Erlotinib and gefitinib are selective
EGFR-TKIs, and numerous clinical studies demonstrated
favorable efficacy and toxicity profiles compared with
T. Kobayashi (&) � T. Koizumi
Comprehensive Cancer Center, Division of Clinical Oncology,
Shinshu University School of Medicine, Shinshu University
Hospital, 3-1-1, Asahi Matsumoto, Matsumoto 390-8621, Japan
e-mail: tomonobu@shinshu-u.ac.jp
T. Agatsuma � M. Yasuo � K. Tsushima � K. Kubo
First Department of Internal Medicine, Shinshu University
School of Medicine, Matsumoto, Japan
S. Eda
Respiratory Division, Matsumoto Kyoritsu Hospital,
Matsumoto, Japan
H. Kuraishi � S. Koyama
Respiratory Division, Nagano Red Cross Hospital,
Nagano, Japan
T. Hachiya
Respiratory Division, Suwa Red Cross Hospital, Suwa, Japan
N. Ohura
Respiratory Division, Saku Central Hospital, Saku, Japan
123
Cancer Chemother Pharmacol (2012) 69:1241–1246
DOI 10.1007/s00280-012-1831-0
cytotoxic chemotherapy [7, 8]. The efficacy of EGFR-TKIs
is associated with EGFR-sensitive mutation status in
NSCLC [5–9]. A high response rate (RR) to EGFR-TKIs is
observed in patients with EGFR-sensitive mutations, but
the RR is 1.0–13.9% in wild-type EGFR [8, 13–15].
In the Iressa Survival Evaluation in Lung Cancer (ISEL)
study, however, gefitinib failed to prolong survival in
unselected patients with advanced NSCLC after failure of at
least one prior chemotherapy regimen [16]. However, in the
same clinical setting study (BR.21) [17], erlotinib showed a
survival advantage of 6.67 months for erlotinib versus
4.70 months for the placebo. Thus, erlotinib is the only
EGFR-TKI shown to provide a survival benefit for
advanced unselected NSCLC patients. In addition, several
clinical studies indicated that erlotinib could confer benefits
in certain patients with NSCLC after gefitinib failure [18,
19]. Thus, erlotinib may have a higher biological activity
and distinct clinical outcomes from gefitinib [20, 21]. Based
on these findings, it is speculated that when treatment with
cytotoxic chemotherapies fails in patients with wild-type
EGFR, erlotinib may be a suitable option for salvage ther-
apy. There is as yet no optimal treatment regimen for
patients with EGFR wild-type NSCLC that has progressed
despite several rounds of cytotoxic chemotherapy.
Therefore, we performed this prospective study to
investigate the efficacy and tolerability of erlotinib mono-
therapy in Japanese patients with wild-type EGFR as a
potential therapeutic option in heavily pretreated NSCLC
patients with progressive disease after treatment with
cytotoxic agents.
Patients and methods
Patient eligibility
Patients eligible for this study were required to have
histologically or cytologically proven stage III/IV or
postoperative recurrent NSCLC without EGFR-sensitive
mutations (exons 18, 19, and 21). The other inclusion cri-
teria were (1) age C20 years old; (2) Eastern Cooperative
Oncology Group (ECOG) performance status (PS) 0–3; (3)
measurable disease according to the Response Evaluation
Criteria in Solid Tumors (RECIST) version 1.0 [22]; (4) no
prior history of EGFR-TKI therapy; and (5) adequate
hepatic and renal function. Patients were excluded from
this study for any of the following reasons: (1) receiving
systemic anticancer therapy within 4 weeks; (2) past his-
tory of hypersensitivity to drugs; (3) severe complications;
(4) active infection; (5) interstitial lung disease (ILD)
detectable on chest radiography; (6) pleural, pericardial, or
peritoneal effusion requiring drainage; (7) active brain
metastasis; or (8) pregnancy. This study was approved by
the institutional review boards of the participating institutes
and was conducted according to the principles of the
Declaration of Helsinki. All enrolled patients gave their
written informed consent.
Pretreatment evaluation
Before enrollment in this study, all patients underwent
clinical and physical examination: PS, medical history,
routine laboratory tests, electrocardiography, chest radi-
ography, computed tomography (CT) scan of the chest and
abdomen, and magnetic resonance imaging (MRI) scan of
the whole brain. Positron emission tomography/CT and
isotope bone scan were performed if medically indicated.
Histological or cytological specimens containing tumor
cells were examined for EGFR mutations by the peptide
nucleic acid-locked nucleic acid polymerase chain reaction
(PNA-LNA PCR) clamp assay. This assay can detect
mutated EGFR sequences with high specificity and sensi-
tivity and is commercially available in Japan.
Treatment protocol
Erlotinib was taken orally at a dose of 150 mg daily. Erl-
otinib therapy was continued until disease progression (PD)
or withdrawal of consent. Erlotinib was interrupted or a
dose reduction considered in patients who developed grade
3 non-hematological toxicities or fever of C38.0�C. In
addition, erlotinib was discontinued under any of the fol-
lowing conditions: (1) development of grade 1 ILD or any
grade 4 toxicity and (2) interruption for over 2 weeks as a
result of over grade 3 toxicity. During the trial, no other
systemic anticancer treatment was permitted.
Toxicity and response evaluation
All toxicities were assessed according to the National
Cancer Institute Common Terminology Criteria for
Adverse Events, version 3.0 [23]. Chest radiography or CT
scan was performed every 2–4 weeks to assess the
response. Complete and partial responses were confirmed
by two observations not less than 4 weeks apart. Deter-
mination of stable disease (SD) required disease stabiliza-
tion for at least 6 weeks in the present study.
Statistical considerations
The primary end point was the disease control rate (DCR).
The expected DCR was 60%, and threshold DCR was 33%.
We estimated that a total of 29 patients would be needed
for the study to have a power of 90% to confirm the
hypothesis with a two-sided significance level of 5%.
Secondary end points were RR, toxicities, progression-free
1242 Cancer Chemother Pharmacol (2012) 69:1241–1246
123
survival (PFS), and overall survival (OS). OS was defined
as the time from enrollment in this study until death from
any cause. PFS was defined as the time from enrollment in
this study to the first observation of PD or death from any
cause. PFS and OS were analyzed by the Kaplan–Meier
method and were compared using the log-rank test. The v2
test was used for comparisons between two groups.
Results
Patient characteristics
A total of 31 patients were enrolled between January 2008
and June 2011 from six institutes in Nagano prefecture,
Japan. The clinical characteristics of the patients are
summarized in Table 1. The median age was 71 years,
with a range of 31–89 years. Most of the patients were men
(74.2%) and were smokers (77.4%). Histological types
included 21 cases of adenocarcinoma (67.7%), nine of
squamous cell carcinoma (29.0%), and one of large cell
carcinoma (3.2%). Ten, nine, eight, and four patients
showed PS 0, 1, 2, and 3, respectively. Two patients were
treated with erlotinib as the first-line chemotherapy
because of advanced age (76 and 84 years old). Eleven
patients were treated with erlotinib as second-line therapy,
and nine cases were treated as third-line therapy. Nine
patients (29.0%) in the present study were treated with
erlotinib as fourth-line or later therapy.
Toxicity and treatment delivery
The adverse event profile is summarized in Table 2. The
most common adverse events associated with erlotinib
treatment were skin rash (80.6%) and diarrhea (38.7%).
Two patients (6.5%) developed ILD, but they recovered
with steroid treatment. Hematological toxicity was not
observed in this study. There were no treatment-related
deaths in the whole study population. Median treatment
duration was 70 days with a range of 10–463 days. Two
patients discontinued erlotinib treatment before response
evaluation because of the development of ILD and patient
refusal, respectively. Dose reduction of erlotinib was per-
formed in five patients (16.1%) because of toxicities
(eruption or diarrhea).
Response and survival
The response to erlotinib was evaluated in all except two
patients because of discontinuation of therapy before
evaluation. The results are shown in Table 3. One patient
achieved a complete response (CR), four showed a partial
response (PR), and eight showed SD; thus, the RR was
17.2% (95% confidence interval (CI): 7.6–35.4%) and
DCR was 44.8% (95% CI: 28.4–62.5%). We also analyzed
the tumor response according to patients’ characteristics
and adverse effects. Patients with a skin rash of grade 2–3
Table 1 Clinical characteristics of all 31 patients
Characteristics No. %
Sex
Male 23 74.2
Female 8 25.8
Age, years
Median 71
Range 31–89
Smoking history
Ever-smoker 24 77.4
Never-smoker 7 22.6
Histology
Adenocarcinoma 21 67.7
Squamous cell carcinoma 9 29.0
Large cell carcinoma 1 3.2
Stage
IIIA 1 3.2
IIIB 9 29.0
IV 14 45.2
Postoperative recurrence 7 22.6
Performance status (PS)
0 10 32.3
1 9 29.0
2 8 25.8
3 4 12.9
No. of prior chemotherapy regimens
0 2 6.5
1 11 35.5
2 9 29.0
3 4 12.9
C4 5 16.1
Table 2 The adverse event profile
Toxicity Grade (No.) All grade (%)
1 2 3 4
Interstitial lung disease (ILD) 0 2 0 0 6.5
Skin rash 3 17 5 0 80.6
Stomatitis 5 0 0 0 16.1
Diarrhea 9 2 1 0 38.7
General fatigue 3 3 0 0 23.1
Appetite loss 0 2 0 0 6.5
Liver dysfunction 2 3 0 0 16.1
Cancer Chemother Pharmacol (2012) 69:1241–1246 1243
123
showed a significantly higher DCR (57.1%) than those with
grade 0 or 1 rash (12.5%, P = 0.02). There were no sig-
nificant differences in DCR in adenocarcinoma and squa-
mous cell carcinoma groups.
Survival was analyzed in all patients, and the survival
curves are shown in Fig. 1. The median PFS and median
survival time (MST) were 2.1 months (95% CI:
0.9–2.8 months) and 7.7 months (3.8–20.4 months),
respectively. One-year survival rate was 44.2% (95% CI:
26.2–63.9%). The PFS and OS in patients with
CR ? PR ? SD were significantly longer than in those
with PD (Fig. 2). In addition, patients with PS 3 had sig-
nificantly shorter PFS (0.4 months) and OS (0.9 months)
than in those with PS 0–2 (PFS: 2.2 months, P = 0.0002
and OS: 10.3 months, P = 0.0002). No significance was
observed in subgroups: gender, smoking history, and
adverse effects. Patients with grade 2–3 rash showed longer
PFS and OS than the group with grade 0 or 1 rash, but the
difference was not significant (PFS, P = 0.15; OS,
P = 0.06). Furthermore, survival tended to be longer in the
adenocarcinoma group than the squamous cell carcinoma
group, but the difference was not significant (P = 0.11).
Discussion
We prospectively evaluated the efficacy and toxicities of
erlotinib in patients with EGFR wild-type NSCLC. In the
present study, we found an objective RR of 17.2%, a
median PFS time of 2.1 months, and MST of 7.7 months,
along with manageable and non-fatal toxicities. As most
patients enrolled in the present study had already received
cytotoxic chemotherapy, the RR of 17.2% and DCR of
44.9% were encouraging results. Thus, we suggest that
Table 3 The response to erlotinib and duration of erlotinib
administration
Parameter No. %
Total no. of patients 31
Response
Complete response (CR) 1 3.4
Partial response (PR) 4 13.8
Stable disease (SD) 8 27.6
Progressive disease (PD) 16 55.2
Not evaluated (NE) 2
Duration of erlotinib administration, days
Median 70
Range 10–463
a b
0
20
40
60
80
100
0 3 6 9 12 15Time (months)
Pro
gres
sion
-fre
e su
rviv
al (
%)
Time (months)
0
20
40
60
80
100
0 6 12 18 24 30
Ove
rall
surv
ival
(%
)
Fig. 1 Kaplan–Meier plot of
progression-free survival
(a) and overall survival (b) after
enrollment in the study. The
median period of progression-
free survival was 2.1 months
(95% CI: 0.9–3.1 months) and
overall survival was 7.7 months
(95% CI: 3.8–20.4 months)
bCR+PR+SD
PD
a
0
20
40
60
80
100
0 3 6 9 12 15
Time (months)
Pro
gres
sion
-fre
e su
rviv
al (
%)
Time (months)
0
20
40
60
80
100
0 6 12 18 24 30
Ove
rall
surv
ival
(%
)
CR+PR+SD
PD
Fig. 2 Kaplan–Meier plot of progression-free survival (a) and overall
survival (b) after enrollment in the study according to the response.
Positive responders (CR ? PR ? SD) had longer median PFS
(4.0 months, 95% CI: 2.6–10.9) than non-responders (0.9 months,
95% CI: 0.4–1.7, P = 0.0001). Positive responders also had longer
median OS (20.4 months, 95% CI: 6.7–not reached) than non-
responders (4.8 months, 95% CI: 1.7–14.6, P = 0.009)
1244 Cancer Chemother Pharmacol (2012) 69:1241–1246
123
EGFR-TKI using erlotinib may be an alternative option for
patients resistant to cytotoxic chemotherapy, even in those
with EGFR wild-type NSCLC.
Wu et al. [14] retrospectively summarized the effec-
tiveness of erlotinib in patients with EGFR wild-type
NSCLC and described the RR of 13.9%. In addition,
Schneider et al. [15] also analyzed the patients from Ger-
man Center in TRUST study [24] and reported a 3%
response to erlotinib in EGFR wild-type cases. Yoshioka
et al. [25] conducted a phase II study prospectively and
reported RR of 3% and DCR of 60% to erlotinib in Japa-
nese patients with EGFR wild-type NSCLC. Compared
with these results, the response rate to erlotinib in the
present study was somewhat higher, although DCR and
PFS were almost identical to these previous reports. As the
number of patients was small in all of these studies,
including the present study, it is difficult to interpret the
differences. Tumor tissues in NSCLC can include histo-
logically heterogeneous components and detection of
positive or resistant EGFR mutant tumor cells may vary
among different tumor sites [26, 27]. As EGFR mutations
were determined at initial diagnosis and not at initiation of
erlotinib treatment, the biological features in the various
sites of tumors may have changed somewhat during cyto-
toxic chemotherapies. Reevaluation of EGFR mutation
may help to determine the variability in the tumors.
The DCR of 44.8% obtained here suggests that treat-
ment with erlotinib would have a significant effect on the
clinical course of patients with EGFR wild-type NSCLC.
We cannot exclude the possibility that the efficacy of erl-
otinib observed in the present study may reflect the natural
history of the disease rather than the efficacy of the drug.
However, the duration of median PFS (4.0 months) in
patients obtained over SD was substantial. The appropriate
treatment in EGFR wild-type NSCLC resistant to several
cytotoxic chemotherapies has yet to be determined. As we
have encountered many patients with no further treatment
options who have progressed despite receiving several
cytotoxic chemotherapies, we emphasize that erlotinib may
be a useful optional treatment for patients with EGFR wild-
type tumors.
In a retrospective analysis comparing the effectiveness
of erlotinib and gefitinib in patients with EGFR wild-type
NSCLC, there are no differences in response rate or sur-
vival rate between the two regimens [14]. As the present
study focused on the efficacy of erlotinib, the superiority or
at least non-inferiority of erlotinib to gefitinib in cases
resistant to multiple cytotoxic chemotherapy regimens was
not determined.
It is difficult to clarify the molecular mechanisms
underlying the effectiveness of erlotinib in this patient
population. Recently, Chang et al. [28] analyzed the
expression of amphiregulin, a novel molecular biomarker,
in patients with EGFR wild-type NSCLC who were treated
with EGFR-TKIs. They reported that, although the rela-
tionship with DCR was not statistically significant, positive
amphiregulin status using immunohistochemical staining
was associated with prolonged PFS and OS. Thus,
amphiregulin could be a potential marker for the selection
of EGFR-TKI treatment in patients with EGFR wild-type
NSCLC. Thus, further studies are warranted to evaluate the
molecular mechanism and clarify how to select patients for
erlotinib treatment among those with EGFR wild-type
NSCLC.
In conclusion, erlotinib is a potentially useful thera-
peutic option for advanced NSCLC patients with EGFR
wild-type tumors showing resistance to cytotoxic chemo-
therapy. Although the molecular mechanisms underlying
the observations of the present study remain unclear, the
results presented here suggest that erlotinib has some
clinical efficacy even in patients with EGFR wild-type
NSCLC.
Conflict of interest None declared.
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